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Kisspeptin Neuron-Specific and Self-Sustained Calcium Oscillation in the Hypothalamic Arcuate Nucleus of Neonatal Mice: Regulatory Factors of its Synchronization.

ABSTRACT: INTRODUCTION:Synchronous and pulsatile neural activation of kisspeptin neurons in the arcuate nucleus (ARN) are important components of the gonadotropin-releasing hormone pulse generator, the final common pathway for central regulation of mammalian reproduction. However, whether ARN kisspeptin neurons can intrinsically generate self-sustained synchronous oscillations from the early neonatal period and how they are regulated remain unclear. OBJECTIVE:This study aimed to examine the endogenous rhythmicity of ARN kisspeptin neurons and its neural regulation using a neonatal organotypic slice culture model. METHODS:We monitored calcium (Ca2+) dynamics in real-time from individual ARN kisspeptin neurons in neonatal organotypic explant cultures of Kiss1-IRES-Cre mice transduced with genetically encoded Ca2+ indicators. Pharmacological approaches were employed to determine the regulations of kisspeptin neuron-specific Ca2+ oscillations. A chemogenetic approach was utilized to assess the contribution of ARN kisspeptin neurons to the population dynamics. RESULTS:ARN kisspeptin neurons in neonatal organotypic cultures exhibited a robust synchronized Ca2+ oscillation with a period of approximately 3 min. Kisspeptin neuron-specific Ca2+ oscillations were dependent on voltage-gated sodium channels and regulated by endoplasmic reticulum-dependent Ca2+ homeostasis. Chemogenetic inhibition of kisspeptin neurons abolished synchronous Ca2+ oscillations, but the autocrine actions of the neuropeptides were marginally effective. Finally, neonatal ARN kisspeptin neurons were regulated by N-methyl-D-aspartate and gamma-aminobutyric acid receptor-mediated neurotransmission. CONCLUSION:These data demonstrate that ARN kisspeptin neurons in organotypic cultures can generate synchronized and self-sustained Ca2+ oscillations. These oscillations controlled by multiple regulators within the ARN are a novel ultradian rhythm generator that is active during the early neonatal period.

SUBMITTER: Kim D

PROVIDER: S-EPMC7592953 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Kisspeptin Neuron-Specific and Self-Sustained Calcium Oscillation in the Hypothalamic Arcuate Nucleus of Neonatal Mice: Regulatory Factors of its Synchronization.

Kim Doyeon D Jang Sangwon S Kim Jeongah J Park Inah I Ku Kyojin K Choi Mijung M Lee Sukwon S Heo Won Do WD Son Gi Hoon GH Choe Han Kyoung HK Kim Kyungjin K

Neuroendocrinology 20200115 11-12

<h4>Introduction</h4>Synchronous and pulsatile neural activation of kisspeptin neurons in the arcuate nucleus (ARN) are important components of the gonadotropin-releasing hormone pulse generator, the final common pathway for central regulation of mammalian reproduction. However, whether ARN kisspeptin neurons can intrinsically generate self-sustained synchronous oscillations from the early neonatal period and how they are regulated remain unclear.<h4>Objective</h4>This study aimed to examine the ...[more]

PMID: 31935735

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Project description:Kisspeptin neurons residing in the rostral periventricular area of the third ventricle (KPRP3V) and the arcuate nucleus (KPARC) mediate positive and negative estrogen feedback, respectively. Here, we aim to compare transcriptional responses of KPRP3V and KPARC neurons to estrogen. Transgenic mice were ovariectomized and supplemented with either 17β-estradiol (E2) or vehicle. Fluorescently tagged KPRP3V neurons collected by laser-capture microdissection were subjected to RNA-seq. Bioinformatics identified 222 E2-dependent genes. Four genes encoding neuropeptide precursors (Nmb, Kiss1, Nts, Penk) were robustly, and Cartpt was subsignificantly upregulated, suggesting putative contribution of multiple neuropeptides to estrogen feedback mechanisms. Using overrepresentation analysis, the most affected KEGG pathways were neuroactive ligand-receptor interaction and dopaminergic synapse. Next, we re-analyzed our previously obtained KPARC neuron RNA-seq data from the same animals using identical bioinformatic criteria. The identified 1583 E2-induced changes included suppression of many neuropeptide precursors, granins, protein processing enzymes, and other genes related to the secretory pathway. In addition to distinct regulatory responses, KPRP3V and KPARC neurons exhibited sixty-two common changes in genes encoding three hormone receptors (Ghsr, Pgr, Npr2), GAD-65 (Gad2), calmodulin and its regulator (Calm1, Pcp4), among others. Thirty-four oppositely regulated genes (Kiss1, Vgf, Chrna7, Tmem35a) were also identified. The strikingly different transcriptional responses in the two neuron populations prompted us to explore the transcriptional mechanism further. We identified ten E2-dependent transcription factors in KPRP3V and seventy in KPARC neurons. While none of the ten transcription factors interacted with estrogen receptor-α, eight of the seventy did. We propose that an intricate, multi-layered transcriptional mechanism exists in KPARC neurons and a less complex one in KPRP3V neurons. These results shed new light on the complexity of estrogen-dependent regulatory mechanisms acting in the two functionally distinct kisspeptin neuron populations and implicate additional neuropeptides and mechanisms in estrogen feedback.

Dataset Information

Kisspeptin Neuron-Specific and Self-Sustained Calcium Oscillation in the Hypothalamic Arcuate Nucleus of Neonatal Mice: Regulatory Factors of its Synchronization.

Publications

Kisspeptin Neuron-Specific and Self-Sustained Calcium Oscillation in the Hypothalamic Arcuate Nucleus of Neonatal Mice: Regulatory Factors of its Synchronization.

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